‘Should I stay or should I go?’ CSHL scientists link brain cell types to behavior

You are sitting on your couch flipping through TV channels trying to decide whether to stay put or get up for a snack. Such everyday decisions about whether to “stay” or to “go” are supported by a brain region called the anterior cingulate cortex (ACC), which is part of the prefrontal cortex. Neuroscientists from Cold Spring Harbor Laboratory (CSHL) have now identified key circuit elements that contribute to such decisions in the ACC.

CSHL Associate Professor Adam Kepecs and his team publish results that, for the first time, link specific brain cell types to a particular behavior pattern in mice – a “stay or go” pattern called foraging behavior. The paper, published online in Nature, shows that the firing of two distinct types of inhibitory neurons, known as somatostatin (SOM) and parvalbumin (PV) neurons, has a strong correlation with the start and end of a period of foraging behavior.

Linking specific neuronal types to well-defined behaviors has proved extremely difficult. “There’s a big gap in our knowledge between our understanding of neuron types in terms of their physical location and their place in any given neural circuit, and what these neurons actually do during behavior,” says Kepecs.

Part of the problem is the technical challenge of doing these studies in live, freely behaving mice. Key to solving that problem is a mouse model developed in the laboratory of CSHL Professor Z. Josh Huang. The mouse has a genetic modification that allows investigators to target a specific population of neurons with any protein of interest.

Kepecs’ group, led by postdocs Duda Kvitsiani and Sachin Ranade, used this mouse to label specific neuron types in the ACC with a light-activated protein – a technique known as optogenetic tagging. Whenever they shone light onto the brains of the mice they were recording from, only the tagged PV and SOM neurons responded promptly with a ‘spike’ in their activity, enabling the researchers to pick them out from the vast diversity of cellular responses seen at any given moment.

The team recorded neural activity in the ACC of these mice while they engaged in foraging behavior. They discovered that the PV and SOM inhibitory neurons responded around the time of the foraging decisions — in other words whether to stay and drink or go and explore elsewhere. Specifically, when the mice entered an area where they could collect a water reward, SOM inhibitory neurons shut down and entered a period of low-level activity, thereby opening a ‘gate’ for information to flow in to ACC. When the mice decided to leave that area and look elsewhere, PV inhibitory neurons fired and abruptly reset cell activity.

“The brain is complex and continuously active, so it makes sense that these two types of inhibitory interneurons define the boundaries of a behavior such as foraging, opening and then closing the ‘gate’ within a particular neural circuit through changes in their activity,” says Kepecs.

This is an important advance, addressing a problem in behavioral neuroscience that scientists call “the cortical response zoo.” When researchers record neural activity in cortex during behavior, and they don’t know which type of neurons they are recording from, a bewildering array of responses is seen. This greatly complicates the task of interpretation. Hence the significance of the Kepecs team’s results, for the first time showing that specific cortical neuron types can be linked to specific aspects of behavior.

“We think about the brain and behavior in terms of levels; what the cell types are and the circuits or networks they form; which regions of the brain they are in; and what behavior is modulated by them,” explains Kepecs. “By observing that the activity of specific cell types in the prefrontal cortex is correlated with a behavioral period, we have identified a link between these levels.”

Clouds in the Head: New Model of Brain’s Thought Processes

A new model of the brain’s thought processes explains the apparently chaotic activity patterns of individual neurons. They do not correspond to a simple stimulus/response linkage, but arise from the networking of different neural circuits. Scientists funded by the Swiss National Science Foundation (SNSF) propose that the field of brain research should expand its focus.

Waiting for a sign? Researchers find potential brain ‘switch’ for new behavior

You’re standing near an airport luggage carousel and your bag emerges on the conveyor belt, prompting you to spring into action. How does your brain make the shift from passively waiting to taking action when your bag appears?

A new study from investigators at the University of Michigan and Eli Lilly may reveal the brain’s “switch” for new behavior. They measured levels of a neurotransmitter called acetylcholine, which is involved in attention and memory, while rats monitored a screen for a signal. At the end of each trial, the rat had to indicate if a signal had occurred.

Researchers noticed that if a signal occurred after a long period of monitoring or “non-signal” processing, there was a spike in acetylcholine in the rat’s right prefrontal cortex. No such spike occurred for another signal occurring shortly afterwards.

"In other words, the increase in acetylcholine seemed to activate or ‘switch on’ the response to the signal, and to be unnecessary if that response was already activated," said Cindy Lustig, one of the study’s senior authors and an associate professor in the U-M Department of Psychology.

The researchers repeated the study in humans using functional magnetic resonance imaging (fMRI), which measures brain activity, and also found a short increase in right prefrontal cortex activity for the first signal in a series.

To connect the findings between rats and humans, they measured changes in oxygen levels, similar to the changes that produce the fMRI signal, in the brains of rats performing the task.

They again found a response in the right prefrontal cortex that only occurred for the first signal in a series. A follow-up experiment showed that direct stimulation of brain tissue using drugs that target acetylcholine receptors could likewise produce these changes in brain oxygen.

Together, the studies’ results provide some of the most direct evidence, so far, linking a specific neurotransmitter response to changes in brain activity in humans. The findings could guide the development of better treatments for disorders in which people have difficulty switching out of current behaviors and activating new ones. Repetitive behaviors associated with obsessive-compulsive disorder and autism are the most obvious examples, and related mechanisms may underlie problems with preservative behavior in schizophrenia, dementia and aging.

The findings appear in the current issue of Journal of Neuroscience.

Complex brain function depends on flexibility

Over the past few decades, neuroscientists have made much progress in mapping the brain by deciphering the functions of individual neurons that perform very specific tasks, such as recognizing the location or color of an object.

However, there are many neurons, especially in brain regions that perform sophisticated functions such as thinking and planning, that don’t fit into this pattern. Instead of responding exclusively to one stimulus or task, these neurons react in different ways to a wide variety of things. MIT neuroscientist Earl Miller first noticed these unusual activity patterns about 20 years ago, while recording the electrical activity of neurons in animals that were trained to perform complex tasks.

“We started noticing early on that there are a whole bunch of neurons in the prefrontal cortex that can’t be classified in the traditional way of one message per neuron,” recalls Miller, the Picower Professor of Neuroscience at MIT and a member of MIT’s Picower Institute for Learning and Memory.

In a paper appearing in Nature on May 19, Miller and colleagues at Columbia University report that these neurons are essential for complex cognitive tasks, such as learning new behavior. The Columbia team, led by the study’s senior author, Stefano Fusi, developed a computer model showing that without these neurons, the brain can learn only a handful of behavioral tasks.

“You need a significant proportion of these neurons,” says Fusi, an associate professor of neuroscience at Columbia. “That gives the brain a huge computational advantage.”

Lead author of the paper is Mattia Rigotti, a former grad student in Fusi’s lab.

Multitasking neurons

Miller and other neuroscientists who first identified this neuronal activity observed that while the patterns were difficult to predict, they were not random. “In the same context, the neurons always behave the same way. It’s just that they may convey one message in one task, and a totally different message in another task,” Miller says.

For example, a neuron might distinguish between colors during one task, but issue a motor command under different conditions.

Miller and colleagues proposed that this type of neuronal flexibility is key to cognitive flexibility, including the brain’s ability to learn so many new things on the fly. “You have a bunch of neurons that can be recruited for a whole bunch of different things, and what they do just changes depending on the task demands,” he says.

At first, that theory encountered resistance “because it runs against the traditional idea that you can figure out the clockwork of the brain by figuring out the one thing each neuron does,” Miller says.

For the new Nature study, Fusi and colleagues at Columbia created a computer model to determine more precisely what role these flexible neurons play in cognition, using experimental data gathered by Miller and his former grad student, Melissa Warden. That data came from one of the most complex tasks that Miller has ever trained a monkey to perform: The animals looked at a sequence of two pictures and had to remember the pictures and the order in which they appeared.

During this task, the flexible neurons, known as “mixed selectivity neurons,” exhibited a great deal of nonlinear activity — meaning that their responses to a combination of factors cannot be predicted based on their response to each individual factor (such as one image).

Expanding capacity

Fusi’s computer model revealed that these mixed selectivity neurons are critical to building a brain that can perform many complex tasks. When the computer model includes only neurons that perform one function, the brain can only learn very simple tasks. However, when the flexible neurons are added to the model, “everything becomes so much easier and you can create a neural system that can perform very complex tasks,” Fusi says.

The flexible neurons also greatly expand the brain’s capacity to perform tasks. In the computer model, neural networks without mixed selectivity neurons could learn about 100 tasks before running out of capacity. That capacity greatly expanded to tens of millions of tasks as mixed selectivity neurons were added to the model. When mixed selectivity neurons reached about 30 percent of the total, the network’s capacity became “virtually unlimited,” Miller says — just like a human brain.

Mixed selectivity neurons are especially dominant in the prefrontal cortex, where most thought, learning and planning takes place. This study demonstrates how these mixed selectivity neurons greatly increase the number of tasks that this kind of neural network can perform, says John Duncan, a professor of neuroscience at Cambridge University.

“Especially for higher-order regions, the data that have often been taken as a complicating nuisance may be critical in allowing the system actually to work,” says Duncan, who was not part of the research team.

Miller is now trying to figure out how the brain sorts through all of this activity to create coherent messages. There is some evidence suggesting that these neurons communicate with the correct targets by synchronizing their activity with oscillations of a particular brainwave frequency.

“The idea is that neurons can send different messages to different targets by virtue of which other neurons they are synchronized with,” Miller says. “It provides a way of essentially opening up these special channels of communications so the preferred message gets to the preferred neurons and doesn’t go to neurons that don’t need to hear it.”

Brain rewires itself after damage or injury

When the brain’s primary “learning center” is damaged, complex new neural circuits arise to compensate for the lost function, say life scientists from UCLA and Australia who have pinpointed the regions of the brain involved in creating those alternate pathways — often far from the damaged site.

The research, conducted by UCLA’s Michael Fanselow and Moriel Zelikowsky in collaboration with Bryce Vissel, a group leader of the neuroscience research program at Sydney’s Garvan Institute of Medical Research, appears this week in the early online edition of the journal Proceedings of the National Academy of Sciences.

The researchers found that parts of the prefrontal cortex take over when the hippocampus, the brain’s key center of learning and memory formation, is disabled. Their breakthrough discovery, the first demonstration of such neural-circuit plasticity, could potentially help scientists develop new treatments for Alzheimer’s disease, stroke and other conditions involving damage to the brain.

For the study, Fanselow and Zelikowsky conducted laboratory experiments with rats showing that the rodents were able to learn new tasks even after damage to the hippocampus. While the rats needed more training than they would have normally, they nonetheless learned from their experiences — a surprising finding.

"I expect that the brain probably has to be trained through experience," said Fanselow, a professor of psychology and member of the UCLA Brain Research Institute, who was the study’s senior author. "In this case, we gave animals a problem to solve."

After discovering the rats could, in fact, learn to solve problems, Zelikowsky, a graduate student in Fanselow’s laboratory, traveled to Australia, where she worked with Vissel to analyze the anatomy of the changes that had taken place in the rats’ brains. Their analysis identified significant functional changes in two specific regions of the prefrontal cortex.

"Interestingly, previous studies had shown that these prefrontal cortex regions also light up in the brains of Alzheimer’s patients, suggesting that similar compensatory circuits develop in people," Vissel said. "While it’s probable that the brains of Alzheimer’s sufferers are already compensating for damage, this discovery has significant potential for extending that compensation and improving the lives of many."

The hippocampus, a seahorse-shaped structure where memories are formed in the brain, plays critical roles in processing, storing and recalling information. The hippocampus is highly susceptible to damage through stroke or lack of oxygen and is critically inolved in Alzheimer’s disease, Fanselow said.

"Until now, we’ve been trying to figure out how to stimulate repair within the hippocampus," he said. "Now we can see other structures stepping in and whole new brain circuits coming into being."

Zelikowsky said she found it interesting that sub-regions in the prefrontal cortex compensated in different ways, with one sub-region — the infralimbic cortex — silencing its activity and another sub-region — the prelimbic cortex — increasing its activity.

"If we’re going to harness this kind of plasticity to help stroke victims or people with Alzheimer’s," she said, "we first have to understand exactly how to differentially enhance and silence function, either behaviorally or pharmacologically. It’s clearly important not to enhance all areas. The brain works by silencing and activating different populations of neurons. To form memories, you have to filter out what’s important and what’s not."

Complex behavior always involves multiple parts of the brain communicating with one another, with one region’s message affecting how another region will respond, Fanselow noted. These molecular changes produce our memories, feelings and actions.

"The brain is heavily interconnected — you can get from any neuron in the brain to any other neuron via about six synaptic connections," he said. "So there are many alternate pathways the brain can use, but it normally doesn’t use them unless it’s forced to. Once we understand how the brain makes these decisions, then we’re in a position to encourage pathways to take over when they need to, especially in the case of brain damage.

"Behavior creates molecular changes in the brain; if we know the molecular changes we want to bring about, then we can try to facilitate those changes to occur through behavior and drug therapy," he added. I think that’s the best alternative we have. Future treatments are not going to be all behavioral or all pharmacological, but a combination of both."

Brainwaves reflect ability to beat built-in bias

Many animals, including humans, harbor ingrained biases to act when they can obtain rewards and to remain inactive to avoid punishment. Sometimes, however those biases can steer us wrong. A new study finds that theta brainwave activity in the prefrontal cortex predicts how well people can overcome these biases when a better choice are available.

Vertebrates are predisposed to act to gain rewards and to lie low to avoid punishment. Try to teach chickens to back away from food in order to obtain it, and you’ll fail, as researchers did in 1986. But humans are better thinkers than chickens. In the May 8 edition of the Journal of Neuroscience, researchers show that the level of theta brainwave activity in the prefrontal cortex predicts whether people will be able to overcome these ingrained biases when doing so is required to achieve a goal.

The study helps explain a distinctly human mechanism of cognition, said the lead researchers at Brown University, and could be applied to studying and treating reward-seeking or punishment-avoidance conditions such as addiction or obsessive-compulsive disorder.

Despite how we have evolved, life doesn’t always encourage acting to gain reward or freezing to avoid punishment. Sometimes we must restrain ourselves to gain a reward (baseball batters can get on base by not swinging at bad pitches) or take action to avoid a penalty (tax cheaters can come forward during amnesties). Acting counter to our ingrained Pavlovian biases is a matter of the brain recognizing the conflict between the rational course of action and the instinct.

“We have suggested that more advanced brain mechanisms in the prefrontal are needed to exert cognitive control over behavior in these circumstances,” said Michael Frank, associate professor of cognitive, linguistic and psychological sciences and the paper’s senior author. “This study provides evidence that temporally specific brain activity within the prefrontal cortex is related to this ability, both between and within individuals.”

Human vs. bias

That brain activity could be measured and quantified as theta brainwaves. Brown postdoctoral researcher James Cavanagh led the research in which he recruited 34 people to play a custom-designed computer game while wearing EEG scalp monitors.

The game involved four scenarios, all reinforced by putting a little real money on the line: the instinctual scenarios of clicking for a reward and not clicking to avoid a penalty, and the trickier scenarios of clicking to avoid penalty and not clicking to gain a reward.

Over many rounds, players tried to learn what to do when presented with one of four distinct symbols, each of which corresponded to a different scenario.

Cavanagh programmed the scenarios usually, but not always, to reward the proper behavior. For this reason, people had to pay attention to what was likely, rather than merely memorize a simple reliable pattern.

Cavanagh and his co-authors measured how well people learned the proper action for each scenario. With the advantage of instinct, almost everyone learned to click for a reward. Most people also managed to learn not to click to avoid penalty and even managed in similar numbers to click to avoid penalty. Like the chickens, however, significantly fewer people could restrain themselves in order to gain a reward.

Those who were bad at overcoming one Pavlovian bias were much more likely to fail at the other.

While the subjects were playing the game, the experimenters also measured theta brainwave activity in each subject’s prefrontal cortex — for instance at the exact moment they saw the distinct symbols of the tasks.

The main idea of the study was to correlate the subjects’ theta brain activity during the tasks with their ability to overcome ingrained bias when appropriate. Sure enough, the subject’s ability to repress Pavlovian bias was predicted by the enhancement of theta during the trials when the bias was unwanted, compared to when it provided proper guidance.

“Some people are really good at it and some are not, and we were able to predict that from their brain activity,” Cavanagh said.

This was not only true when comparing individual subjects, but also when comparing the subjects to themselves at different times (e.g., some subjects’ abilities wavered from task to task and the theta varied right along).

Many psychological factors could have confounded the results — differential sensitivity to gains and losses, for example – but Cavanagh and Frank controlled for those with the help of a sophisticated computer model that accounts for and statistically disentangles the relationship of bias and theta from those other influences.

Our better nature

All of the study subjects were screened to ensure they were psychiatrically healthy. In these subjects, the study results not only confirmed that people harbor the ingrained biases, but that they differ in their ability to overcome them. Frank said the variations likely come from innate and situational factors. Evidence suggests that the degree of ingrained bias may have genetic and neurological roots, he said, but can also vary within the same individual based on factors such as fatigue or stress.

For people with psychiatric disorders, Cavanagh said, the predictive value of measurable theta activity for behavioral patterns could become an important tool for diagnosis and predicting treatment outcomes.

Frank, who is affiliated with the Brown Institute for Brain Science, added that the lab has begun studying whether people can improve behavior by purposely modulating theta activity. If so, that could lead to a therapy for addiction.

“We are beginning studies that allow us to safely manipulate activity in specific frequencies like theta in the frontal cortex which will allow us to assess the causal role these signals may be playing,” he said.

It’s not easy to work against primal intuition, but people have that ability and now researchers know how that ability is reflected in brains.

“This tells us a lot about the neurobiology of why we’re special,” Cavanagh said.